Abstract
Two megalencephaly (MEG) syndromes, megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyriapolydactyly-hydrocephalus (MPPH), have recently been defined on the basis of physical and neuroimaging features. Subsequently, exome sequencing of ten MEG cases identified de-novo postzygotic mutations in PIK3CA which cause MCAP and de-novo mutations in AKT and PIK3R2 which cause MPPH. Here we present findings from exome sequencing three unrelated megalencephaly patients which identified a causal PIK3CA mutation in two cases and a causal PIK3R2 mutation in the third case. However, our patient with the PIK3R2 mutation which is considered to cause MPPH has a marked bifrontal band heterotopia which is a feature of MCAP. Furthermore, one of our patients with a PIK3CA mutation lacks syndactyly/polydactyly which is a characteristic of MCAP. These findings suggest that the overlap between MCAP and MPPH may be greater than the available studies suggest. In addition, the PIK3CA mutation in one of our patients could not be detected using standard exome analysis because the mutation was observed at a low frequency consistent with somatic mosaicism. We have therefore investigated several alternative methods of exome analysis and demonstrate that alteration of the initial allele frequency spectrum (AFS), used as a prior for variant calling in samtools, had the greatest power to detect variants with low mutant allele frequencies in our 3 MEG exomes and in simulated data. We therefore recommend non-default settings of the AFS in combination with stringent quality control when searching for causal mutation(s) that could have low levels of mutant reads due to post-zygotic mutation.
Highlights
Syndromes (MEG) have been noted to arise as sporadic overgrowth disorders and have been associated with variable additional malformations including cortical dysplasia, developmental vascular anomalies, distal limb malformations and variable connective tissue dysplasias [1]
Identification of Causal Variants in PIK3CA and PIK3R2 We examined exome data from three Megalencephaly syndromes (MEG) cases for the mutations in AKT3, PIK3R2, and PIK3CA which had been identified as causal [2]
All methods used correctly identified the causal variant in patient 1, who is heterozygous for the PIK3CA c.2176G.A, p.E726K variant, and in patient 3 who is heterozygous for the PIK3R2 c.1117G.A, p.G373R variant (Table 2)
Summary
Syndromes (MEG) have been noted to arise as sporadic overgrowth disorders and have been associated with variable additional malformations including cortical dysplasia, developmental vascular anomalies, distal limb malformations and variable connective tissue dysplasias [1]. Recent findings led to the characterisation of two MEG syndromes on the basis of physical and neuroimaging anomalies [1] In the case of syndromes for which mosaic skin defects are a feature, the concept of a lethal gene surviving by mosaicism was first suggested in 1987 [3]. Such mutations would lead to early embryonic death when present in the zygote but mutated cells could survive if in close proximity to normal cells and the mutation could arise, for example, as an early somatic mutation. The authors identified tissues and cell lines from patients with Proteus syndrome as having admixtures of mutant alleles ranging from 1%–50%
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